Imbruvica®▼ (ibrutinib) Long-Term Data from Two Pivotal Phase 3 Studies at ASCO and EHA Demonstrate Sustained Efficacy and Safety in Patients with Chronic Lymphocytic Leukaemia (CLL)

The Janssen Pharmaceutical Companies of Johnson & Johnson today announced long-term follow-up results from two pivotal Phase 3 studies of Imbruvica^® (ibrutinib) in patients with chronic lymphocytic leukaemia (CLL), a type of non-Hodgkin lymphoma and the most common form of leukaemia in adults.³ One set of data – results from the RESONATE^TM study (PCYC-1112) at a median follow-up of 65.3 months (range, 0.3–71.6) – showed treatment with ibrutinib monotherapy sustained progression-free survival (PFS) benefit compared to ofatumumab in patients with previously treated CLL, with a median PFS of 44.1 months versus 8.1 months, respectively.¹ A consistent PFS benefit with ibrutinib was observed across all baseline disease and patient characteristics, including patients with genomically defined high-risk disease.¹ The median overall survival (OS) was 67.7 months in the ibrutinib arm and 65.1 months in the ofatumumab arm, without censoring or adjustment for crossover from ofatumumab to ibrutinib.¹ Additionally, no new safety events were identified in this long-term follow-up.¹ The RESONATE^TM results were presented today at the 55^th American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, and selected for the Best of ASCO 2019 Meetings, which highlight cutting-edge science and reflect leading research in oncology (abstract #7510).

The second data set – results from the RESONATE^TM-2 study (PCYC-1115/1116) at a median follow-up of five years (range, 0.1–66 months) – demonstrated durable PFS with ibrutinib monotherapy (estimate of 70 percent) versus chlorambucil (estimate of 12 percent) in patients with previously untreated CLL, including those with genomically defined high-risk disease.² The OS benefit was also sustained in patients treated with ibrutinib (estimate of 83 percent) versus chlorambucil (estimate of 68 percent). In addition, no new safety concerns were observed.² The RESONATE^TM-2 data will be presented in full during an oral presentation at the 24^th European Hematology Association (EHA) Congress in Amsterdam on Friday, June 14 (abstract #S107).²

“Since its first European approval in 2014, ibrutinib has redefined treatment paradigms for CLL, and these study results offer further evidence to both clinicians and patients of the longer-term benefits and tolerability ibrutinib offers as a single agent,” said Peter Hillmen, MB ChB, PhD, Professor of Experimental Haematology and Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust, United Kingdom and investigator in both studies. “Not only is superior progression-free survival and overall survival maintained with ibrutinib follow-up, but frequently the quality of response rates improves from partial to complete over time.”

“Ibrutinib has already impacted more than 140,000 patients, and the RESONATE and RESONATE-2 long-term follow-up studies provide important data in support of its continued use in the effective management of CLL,” said Dr Patrick Laroche, Europe, Middle East and Africa (EMEA) Haematology Therapeutic Area Lead, Janssen-Cilag France. “We are excited to explore how best this BTK inhibitor can continue to enhance the lives of people living with CLL, both as a monotherapy and in newer combination regimens, and as an alternative option to intensive chemotherapy.”

Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is jointly developed and commercialised by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.

ASCO: RESONATE ^TM six-year follow-up of ibrutinib monotherapy in patients with previously treated CLL ( Abstract #7510 ) ¹

The RESONATE^TM (PCYC-1112) study evaluated patients with previously treated CLL who were randomised to receive ibrutinib 420 mg orally once daily until disease progression or intravenous ofatumumab for up to 24 weeks (n=391); 86 percent and 79 percent, respectively, were in the genomically defined high-risk population (17p deletion, 11q deletion, TP53 mutation, and/or unmutated IGHV).¹ Long-term efficacy endpoints were investigator-assessed.¹

With up to six years of follow-up (median 65.3 months, range, 0.3–71.6 months), extended ibrutinib treatment showed sustained efficacy in patients with previously treated CLL, including patients with high-risk genomic features, with no new safety signals over long-term therapy.¹

Of the patients receiving ofatumumab, 68 percent crossed over to receive ibrutinib.¹ A statistically significant PFS benefit was sustained with ibrutinib versus ofatumumab, with median PFS of 44.1 months versus 8.1 months (hazard ratio [HR]=0.15; 95 percent confidence interval [CI], 0.11–0.20, P˂0.0001), and was consistent across baseline subgroups.¹ Median PFS in the genomically defined high-risk population was 44.1 months versus 8.0 months on ibrutinib versus ofatumumab (HR=0.11; 95 percent CI, 0.08–0.15).¹

The median OS was 67.7 months in the ibrutinib arm and 65.1 months in the ofatumumab arm, without censoring or adjustment for crossover from ofatumumab to ibrutinib (HR=0.81; 95 percent CI, 0.60-1.09).¹ Sensitivity analysis adjusting for crossover based on the rank-preserving structural failure time (RPSFT) method also showed continued OS benefit with ibrutinib compared to ofatumumab (HR=0.24; 95 percent CI, 0.11-0.55).¹ The overall response rate (ORR) with ibrutinib was 91 percent, with 11 percent achieving a complete response (CR/CR with incomplete blood recovery [CRi]).¹ Median treatment duration of ibrutinib was 41 months; 40 percent of patients received ibrutinib for longer than four years.¹

The adverse event (AE) profile with ibrutinib remained consistent with prior studies.¹ The prevalance of any Grade 3 or higher AEs with ibrutinib decreased after the first year and remained stable thereafter. All Grade and Grade 3 or higher AEs, respectively, included hypertension (21 percent; 9 percent) and atrial fibrillation (12 percent; 6 percent); major haemorrhage occurred in 10 percent.^1,4 The most common reasons for ibrutinib discontinuation prior to study closure were progressive disease (37 percent) and AEs (16 percent).¹

EHA: RESONATE ^TM -2 five-year follow-up of ibrutinib monotherapy in patients with previously untreated CLL ( Abstract #S107 ) ²

The RESONATE^TM-2 (PCYC-1115/1116) study evaluated patients 65 years or over with previously untreated CLL, without 17p deletion, who received ibrutinib 420 mg orally once-daily continuously until disease progression or unacceptable toxicity, or chlorambucil 0.5–0.8 mg/kg orally for up to 12 cycles (n=269).²

Results from this five-year follow-up showed ibrutinib monotherapy sustained PFS and OS benefits for patients with CLL versus chlorambucil, including those with high-risk genomic features.² More than half of patients remain on long-term continuous treatment with ibrutinib. Additionally, no new safety concerns were identified.²

At a median follow-up of 60 months (range, 0.1–66 months), the PFS benefits were sustained in patients treated with ibrutinib (estimate of 70 percent) versus chlorambucil (estimate of 12 percent) (HR=0.15; 95 percent CI, 0.10–0.22).² The OS benefits were also sustained in patients treated with ibrutinib (estimate of 83 percent) versus chlorambucil (estimate of 68 percent).² Ibrutinib improved PFS compared with chlorambucil in patients with unmutated IGHV (HR=0.11; 95 percent CI, 0.06–0.19) and in patients with 11q deletion (HR=0.03; 95 percent CI, 0.01–0.11).² Additionally, 57 percent of patients crossed over from chlorambucil to ibrutinib after progression.²

As a composite, patients with high-risk genomics (unmutated IGHV, 11q deletion, and/or TP53 mutation) had superior outcomes with ibrutinib compared with chlorambucil (PFS: HR=0.08; 95 percent CI, 0.05–0.15; OS: HR=0.37; 95 percent CI, 0.18–0.74).² With ibrutinib, the ORR including partial response with lymphocytosis was 92 percent and the CR/CRi rate increased over time to 30 percent (from 11 percent CR/CRi at primary analysis at median follow-up of 18 months).²

The most common Grade 3 or higher AEs included neutropenia (13 percent), pneumonia (12 percent), hypertension (8 percent), anaemia (7 percent), hyponatremia (6 percent), atrial fibrillation (5 percent), and cataract (5 percent), with rates of most events decreasing over time.² Dose reductions due to Grade 3 or higher AEs decreased over time. Benefit with ibrutinib treatment continued in 58 percent of patients who remained on therapy at the time of this analysis.²

#ENDS#

About ibrutinib

Ibrutinib is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, which works by forming a strong covalent bond with BTK to block the transmission of cell survival signals within the malignant B-cells.⁵ By blocking this BTK protein, ibrutinib decreases survival and migration of B lymphocytes, thereby delaying the progression of the cancer.⁶

Ibrutinib is currently approved in Europe for:⁷

• Chronic lymphocytic leukaemia (CLL): As a single agent for the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have received at least one prior therapy.
• Mantle cell lymphoma (MCL): Adult patients with relapsed or refractory mantle cell lymphoma.
• Waldenström’s macroglobulinemia (WM): Adult patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemo-immunotherapy.

Ibrutinib is approved in more than 90 countries, and, to date, has been used to treat more than 140,000 patients worldwide across its approved indications.

The most common adverse reactions seen with ibrutinib include diarrhoea, neutropenia, haemorrhage (e.g., bruising), musculoskeletal pain, nausea, rash, and pyrexia.⁷

For a full list of side effects and information on dosage and administration, contraindications and other precautions when using ibrutinib please refer to the Summary of Product Characteristics for further information.

About the Janssen Pharmaceutical Companies of Johnson & Johnson

At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Learn more at www.janssen.com/emea. Follow us at www.twitter.com/janssenEMEA for our latest news. Janssen Research & Development, LLC., Janssen Biotech, Inc., and Janssen-Cilag France are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Cautions Concerning Forward-Looking Statements

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding IMBRUVICA ^® (ibrutinib). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC., Janssen-Cilag France and any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; [product efficacy or safety concerns resulting in product recalls or regulatory action;] changes in behaviour and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2018, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q, and the company’s subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov , www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

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¹ Barr P, Munir T, Brown J, et al. Final analysis from RESONATE^TM: Six-year follow-up in patients (pts) with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) on ibrutinib. Poster presentation at 55th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, USA, 31 May–4 June 2019.
² Tedeschi A, Burger J, Barr PM, et al. Five-year follow-up of patients receiving ibrutinib for first-line treatment of Chronic Lymphocytic Leukemia. Abstract S107. Available at: https://learningcenter.ehaweb.org/eha/2019/24th/267308/alessandra.tedeschi.five-year.follow-up.of.patients.receiving.ibrutinib.for.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Dibrutinib+five+year. Last accessed May 2019.
³ American Cancer Society. What Is Chronic Lymphocytic Leukemia? Available at: https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html. Last accessed May 2019.
⁴ Barr P, Munir T, Brown J, et al. Final analysis from RESONATE^TM: Six-year follow-up in patients (pts) with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) on ibrutinib. Abstract J Clin Oncol 37, 2019 (suppl; abstr 7510) Available at: http://abstracts.asco.org/239/AbstView_239_249511.html. Last accessed May 2019.
⁵ O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15:48-58.
⁶ European Medicines Agency. Imbruvica (ibrutinib): an overview of Imbruvica and why it is authorised in the EU. Available at: https://www.ema.europa.eu/documents/overview/imbruvica-epar-summary-public_en.pdf Last accessed May 2019.
⁷ Imbruvica Summary of Product Characteristics, May 2019. Available at: https://www.ema.europa.eu/documents/product-information/imbruvica-epar-product-information_en.pdf Last accessed May 2019.

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June 2019

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